The central hypothesis of the present proposal is that in response to appropriate stimuli, glomeruli generate reactive oxygen species which may be important in the functional and morphological changes in various glomerulopathies. This hypothesis is based on: the well documented presence of phagocytic cells in glomeruli; production of reactive oxygen species in response to a stimulus by other phagocytic cells; and recent evidence that reactive oxygen species affect a variety of biological processes potentially important in glomerular diseases. Preliminary studies showing that isolated rat glomeruli generate reactive oxygen species (as quantified by chemiluminescence (CL)) in response to a soluble stimulus (phorbal myristate acetate) lend strong support to this hypothesis. The objectives of this proposal are the following: A.1. The reactive oxygen species responsible for CL will be identified using enzymic and chemical scavengers; 2. Metabolic events responsible for and associated with CL response will be studied by use of metabolic inhibitors, measurement of oxygen uptake and oxidation of specifically labeled glucose. Factors which affect the CL response also will be examined. B. Free reactive oxygen species have been shown to affect stability of liver lysosomes. In view of this the effect of free radicals formed in situ and in vitro superoxide generating system on glomerular lysosomes as well as the modulatory role of cAMP and cGMP will be examined. C. The importance of reactive oxygen species in glomerular disease will be studied by measuring their production in animal models of renal disease; and by examining the effects of scavengers of reactive oxygen species on the functional and morphological changes in renal diseases. Demonstration of role of reactive oxygen species in glomerular diseases has immense clinical implications since scavengers of free radicals are readily available and have low level of toxicity.